Alzheimer's disease (AD) is a devastating illness, estimated to affect 5 million patients in the United States alone and projected to increase dramatically over the next decades as the population ages unless preventive measures can be developed. In the revised application we respond to PAR-11-100 Alzheimer's Disease Pilot Clinical Trials to outline a pilot clinical trial to answer critical questions before proceeding toa larger scale, definitive prospective trial. We will establish measures of drug efficacy in CSF as well as refine the target population. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower A plaques in the human brain. We have investigated the possible mechanism for this reduction in amyloid plaque burden by measuring the effect of SSRI antidepressants on A levels in a transgenic mouse model of AD. Three common SSRI antidepressants acutely reduced brain extracellular A levels by 25% in vivo. Furthermore, chronic treatment with an SSRI, citalopram, for 4 months significantly reduced hippocampal and cortical plaque burden by 42.3% and 50.7%, respectively. We will conduct a stratified, randomized placebo controlled trial of 54 cognitively normal participants, age 65- 80, (Clinical Dementia Rating scale, [CDR] = 0) recruited from the Washington University ADRC. Participants will have undergone full clinical evaluation and PET amyloid imaging. Prior to randomization they will be stratified by APOE4 status. Participants will be randomized (18 per group) to acute treatment with placebo, 20 mg citalopram or 40 mg citalopram. Participants will receive non-radioactive 13C6-leucine administration and CSF sampling with assessment of A production during a 36-hour stay in our clinical research unit. To yield n = 18 participants per group with analyzable data, we will recruit n = 60 subjects, allowing for the 10% dropout rate that has been experienced in prior SILK studies. We will determine: 1) whether SSRI administration results in reduced CSF A production (Aim 1); 2) whether a dose of citalopram 20 mg as well as citalopram 40 mg dose results in A reduction (Aim 2); and 3) explore whether there is an effect of APOE status or age on A reduction (Aim 3). Significance: If citalopram is associated with a substantial reduction in A generation, we wil use this data to plan a prospective clinical trial to test whether chronic use of SSRI reduces the rate of A plaque formation. While many factors go into the design of such a trial, given that SSRIs are among the best-tolerated neuroactive drug classes approved by the FDA and could be readily tested in a clinical trial, the potential significance for AD prevention would be rapid and large. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating illness, projected to increase dramatically over the next decades unless preventive measures can be developed. In the current revised application we respond to PAR-11-100 Alzheimer's Disease Pilot Clinical Trials to outline a pilot clinical trial to answer critical questions before proceeding to a larger scale, definitive prospective trial. We have preliminary evidence that selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with lower amyloid binding in the human brain. We will conduct a randomized placebo controlled trial of 54 cognitively normal participants, age 65-80, (Clinical Dementia Rating scale, [CDR] = 0) recruited from the Washington University ADRC. Participants will be randomized (18 per group) to acute treatment with placebo, 20 mg citalopram or 40 mg citalopram. Participants will receive non-radioactive 13C6-leucine administration and CSF sampling with assessment of A production during a 36-hour stay in our clinical research unit. We will determine: whether SSRI administration results in reduced CSF A production (Aim 1); whether citalopram 20mg dose as well as citalopram 40 mg dose are associated with A reduction (Aim 2); and explore whether APOE4 status and age influence A reduction (Aim 3). Significance: If citalopram is associated with a substantial reduction in A generation, we will use this data to plan a prospective clinical trial to test whether chronic use of SSRI reduces the rate of A plaque formation. While many factors go into the design of such a trial, given that SSRIs are among the best-tolerated neuroactive drug classes approved by the FDA and could be readily tested in a clinical trial, the potential significance for AD prevention would be large.